Class II major histocompatibility complex (MHC) molecules, constitutively expressed on normal antigen presenting cells (APC), are responsible for the presentation of antigen-derived peptides to CD4+ helper T (Th) cells. Babbitt et al., Nature 317:359-361 (1985) and Truman et al., Blood 89(6):1996-2007 (1997). Signaling via these molecules initiates the generation of second messengers leading to programmed cell death (PCD or apoptosis) of activated B lymphocytes. Besides antigen presentation, class II molecules transduce signals that can modulate cell growth and certain class II MHC-specific monoclonal antibodies have been shown to induce apoptosis of cancer cells. Newell et al., Proc. Natl. Acad. Sci. U.S.A. 90(22):10459-10463 (1993).
HLA class II molecules are constitutively expressed on human B lymphocytes and are induced on human T lymphocytes after activation. Up to 60% of cell death has been observed after stimulation of lymphocytes via HLA-DR molecules. Certain HLA-DR-specific antibodies cause up to a 90% decrease in the cell surface expression of class II molecules. HLA-DR-specific antibodies and fragments thereof do not affect the expression of HLA-DP and HLA-DQ molecules. Truman, et al., Int. Immunol. 6(6):887-896 (1994).
Class II M HC-specific antibodies that have been shown to induce apoptosis of cancer cells frequently also interfere with normal Th cell functions. Vidovic et al., Eur. J. Immunol. 25:3349-3355 (1995). The majority of currently available apoptosis-inducing class II-specific monoclonal antibodies recognize epitopes located on the first protein domains of the HLA-DR heterodimer, in apparent close proximity to the peptide-binding site, and these antibodies interfere with antigen presentation, causing a potent in vitro and in vivo inhibition of Th responses, in addition to being cytotoxic for B lymphoblastoid cell lines and for a small proportion of normal activated B cells. Their F(ab′)2 fragments mediate both down-regulation and cytotoxicity, whereas their monovalent Fab fragments are not cytotoxic, but retain the down-regulatory and T cell inhibitory properties. Id.
Thus, most HLA-DR-specific apoptotic monoclonal antibodes available in the art exhibit sufficient immunosuppressive activity to limit their utility in compositions and methods for the treatment of cancers involving HLA-DR-positive cells. Accordingly, there remains a need in the art for improved HLA-DR-specific antibodies, such as for example non-immunosuppressive apoptotic HLA-DR-specific antibodies, as well as compositions and methods comprising such antibodies that overcome these deficiencies.